Topical Glutathione Formulations For Menopausal Skin

ABSTRACT

Topical compositions to address menopausal skin conditions comprise an effective amount of S-acyl glutathione derivative and a carrier. Methods for addressing menopausal skin conditions comprise applying a composition containing S-acyl glutathione derivative in a dermatologically acceptable carrier to skin tissue. The acyl group is a saturated or unsaturated aliphatic C 12 -C 24  group, preferably an unsaturated C 16 -C 24  group, most preferably an unsaturated C 18  group. In particularly preferred embodiments, the acyl group is a linoleoyl group.

FIELD OF THE INVENTION

The present invention relates to topical compositions to improve theappearance of menopausal skin. More specifically, the present inventionrelates to topical compositions comprising acyl derivatives ofglutathione to address severe skin dryness, dullness, loss ofelasticity, or lack of radiance or to prevent or retard the appearanceof exaggerated lines and wrinkles or spider vessels or red blotchiness,all visible conditions of peri-menopausal, menopausal, orpost-menopausal skin.

BACKGROUND OF THE INVENTION

Reduced glutathione, most commonly called glutathione or GSH, is arelatively small molecule found in animals and plants, having thefollowing formula:

Glutathione is a water-phase orthomolecule. It is the smallestintracellular thiol molecule. It is a potent reducing compound due toits significant electron-donating capacity. Glutathione is a potentantioxidant and enzyme cofactor which plays a critical role inregulating cell activity.

Glutathione is a linear tripeptide of L-glutamine, L-cysteine, andglycine. Technically, N-L-gamma-glutamyl-cysteinyl glycine orL-glutathione, the molecule has a sulfhydryl (SH) group on the cysteinylportion, which accounts for its strong electron-donating character. Aselectrons are lost, the molecule becomes oxidized, and two oxidizedglutathione molecules become linked (dimerized) by a disulfide bridge toform glutathione disulfide or oxidized glutathione (GSSG). This linkageis reversible upon re-reduction. Glutathione is under tight homeostaticcontrol both intracellularly and extracellularly. A dynamic balance ismaintained between glutathione synthesis, its recycling fromGSSG/oxidized glutathione, and its utilization.

Glutathione synthesis involves two closely linked, enzymaticallycontrolled reactions that utilize ATP. First cysteine and glutamate arecombined by gamma-glutamyl cysteinyl synthetase. Second, glutathionesynthetase combines gamma-glutamylcysteine with glycine to generateglutathione. As glutathione levels rise, they self-limit furtherglutathione synthesis; otherwise, cysteine availability is usuallyrate-limiting. Fasting, protein-energy malnutrition, or other dietaryamino acid deficiencies limit glutathione synthesis.

Glutathione recycling is catalyzed by glutathione disulfide reductase,which uses reducing equivalents from NADPH to reconvert GSSG to 2GSH.The reducing power of ascorbate helps conserve systemic glutathione.Glutathione is used as a cofactor by (1) multiple peroxidase enzymes, todetoxify peroxides generated from oxygen radical attack on biologicalmolecules; (2) transhydrogenases, to reduce oxidized centers on DNA,proteins, and other biomolecules; and (3) glutathione S-transferases(GST) to conjugate glutathione with endogenous substances (e.g.,estrogens) and to exogenous electrophiles (e.g., arene oxides,unsaturated carbonyls, organic halides), and diverse xenobiotics.

Free radical and other oxidative agents can deplete glutathione. Thehomeostatic glutathione redox cycle attempts to maintain glutathionelevels as it is being consumed. Amounts available from foods are limited(less than 150 mg/day), and oxidative depletion can outpace synthesis.

The liver is the largest glutathione reservoir. The parenchymal cellssynthesize glutathione for P450 conjugation and numerous other metabolicrequirements, then export glutathione as a systemic source ofSH/reducing power. Glutathione is carried in the bile to the intestinalluminal compartment. Epithelial tissues of the kidney tubules,intestinal lining, and lung, have substantial P450 activity and modestcapacity to export glutathione.

Glutathione equivalents circulate in the blood predominantly ascysteine, the oxidized and more stable form of cysteine. Cells importcysteine from the blood, reconvert it to cysteine (likely usingascorbate as cofactor), and from it synthesize glutathione. Conversely,inside the cell glutathione helps re-reduce oxidized forms of otherantioxidants such as ascorbate and alpha-tocopherol.

Glutathione is an extremely important cell protectant. It directlyquenches reactive hydroxyl free radicals, other oxygen-centered freeradicals, and radical centers on DNA and other biomolecules. Glutathioneprotects skin, lens, cornea, and retina against radiation damage, andthe biochemical foundation of P450 detoxication in the liver, kidneys,lungs, intestinal epithelia, and other organs.

Glutathione is the essential cofactor for many enzymes which requirethiol-reducing equivalents, and helps keep redox-sensitive active siteson enzymes in the necessary reduced state. Higher-order thiol cellsystems—the metallothioneins, thioredoxins, and other redox regulatorproteins—are ultimately regulated by GSH levels and the GSH/GSSG redoxratio.

Glutathione and its metabolites also interface with energetics andneurotransmitter syntheses, through several prominent metabolicpathways. Glutathione availability down-regulates the pro-inflammatorypotential of leukotrienes and other eicosanoids.

Glutathione levels in human tissues normally range from 0.1 to 10millimolar (mM), most concentrated in the liver (up to 10 mM) and in thespleen, kidney, lens, erythrocytes, and leukocytes. Plasma concentrationis in the micromolar range (approx. 4.5 μM). Oxidative stressors thatcan deplete glutathione include ultraviolet and other radiation; viralinfections; environmental toxins, household chemicals, and heavy metals;surgery, inflammation, burns, septic shock; and dietary deficiencies ofglutathione precursors and enzyme cofactors.

A number of disclosures teach enhancing the cellular level ofglutathione through administration of various glutathione derivatives.U.S. Pat. No. 5,464,825 (Anderson) discloses use of N-acyl monoalkylglutathione monoester for increasing cellular levels in the liver andkidney cells to treat AIDS and other viral infections. U.S. Pat. No.5,624,955 (Nagasawa) discloses glutathione prodrugs consisting ofglutamyl cysteine derivatives to enhance glutathione level in the lensand prevent cataract onset. U.S. Pat. No. 7,029,695 (Redelmeier)discloses lipid formulations to enhance the bioavailability of analogsof glutathione for use in hematopoiesis modulation. Neuroscience138:1161-1170 (2006) (Perluigi et al.) discloses use ofTricyclodecan-9-yl-xanthogenate to achieve an increase in glutathionelevels in the neuronal cells to treat Alzheimer's disease WO 2009/047728(Liguri) discloses that lipophilic derivatives of glutathione may beuseful in treating Alzheimer disease and Huntington chorea.

Topical uses of glutathione derivatives have been disclosed. U.S. Pat.No. 3,984,569 (Kalopissis) discloses use of S-substituted linear andbranched alkyl and alkenyl derivatives of glutathione for various scalpand hair applications and to combat excessive sebum secretion. U.S. Pat.No. 5,516,507 (N'Guyen) discloses glutathione mono-alkyl esters fortopical treatment of cutaneous aging. These glutathione mono-alkylesters are substituted at the glycine residue and employ alkyl chainshaving only 1 to 10 carbons. U.S. Pat. App. 2004/0147452 (Yu) proposesthe use of non-amphoteric N-acyl glutathione derivatives for topicalapplication for a broad range of conditions. The non-amphotericderivatives of glutathione are proposed due to the instability ofaqueous pharmaceutical formulations of mono and diester prodrugs ofglutathione, which rapidly deteriorate over time.

U.S. Pat. No. 6,011,067 (Hersh) discloses compositions as adjuncts totopical therapy of desquamating inflammatory disorders, such aspsoriasis, which compositions contain as active ingredientsL-glutathione and a selenium compound. Hersh's disclosure stresses theimportance of the presence of both ingredients to the anti-psoriaticeffectiveness of the claimed composition.

My published applications, U.S. Patent Publications Nos. 20050192229,20060063718; and 20060069036 disclose compositions with high glutathioneconcentrations for topical use in the treatment of psoriasis.

SUMMARY OF THE INVENTION

The present invention provides topical compositions to addressconditions experienced by women in the menopausal state comprising acarrier and an effective amount of S-acyl glutathione derivative of thefollowing formula:

wherein R₁ is consists of a saturated or unsaturated aliphatic C₁₂-C₂₄group, preferably an unsaturated C₁₆-C₂₄ group, more preferably anunsaturated C₁₈ group, most preferably, a linoleoyl group; and R₂ is ahydrogen, aliphatic or aromatic acyl group, preferably a hydrogen.

Methods for improving the condition, preventing or treating menopausalskin comprise applying a composition containing an effective amount ofS-acyl glutathione derivative in a dermatologically acceptable carrierto skin.

More specifically, the present invention provides topical compositionsand methods of applying compositions comprising acyl derivatives ofglutathione to address severe skin dryness, dullness, loss ofelasticity, or lack of radiance or to prevent or retard the appearanceof exaggerated lines and wrinkles or spider vessels or red blotchiness,all visible conditions of peri-menopausal, menopausal, orpost-menopausal skin.

DETAILED DESCRIPTION OF THE INVENTION

Aging of the skin is often caused by the loss of estrogen or decline inoestrogen associated with menopause. Oestrogen receptors are mostabundant around the face, genital area and lower limbs. The presentinvention recognizes this process and provides a composition and methodto minimize both prospective and existing skin conditions associatedwith loss of estrogen and oestrogen during menopause.

The term “skin” means the keratinous surfaces skin, hair and nails. Theterm “skin” when used herein is in the broad sense meaning the skin ofthe face, body, and neck as well as the lips.

The present invention comprises topical S-acyl glutathione (GSH)compositions to prevent skin aging and address skin conditionsassociated with menopause. The compositions help address severe skindryness, dullness, loss of elasticity, or lack of radiance exaggeratedlines and wrinkles or spider vessels or red blotchiness. Thesecompositions may also be referred to using IUPAC nomenclature asS-alkanoyl glutathione compositions. The treatments consist of S-acylglutathione derivatives of the formula:

wherein R₁ is consists of a saturated or unsaturated aliphatic C₁₂-C₂₄group, preferably a unsaturated C₁₆-C₂₄ group, preferably an unsaturatedC₁₈ group; and R₂ is a hydrogen, aliphatic or aromatic acyl group, andmost preferably a hydrogen group. In particularly preferred embodiments,R₁ is selected from the group consisting of linoleoyl or oleoyl groups,but is most preferably a linoleoyl group. The preferred embodiment ofthe invention is thus S-linoleoyl glutathione.

A particular object of the present invention is to provide S-acylglutathione compositions having acyl groups to enhance skin penetrationand transdermal absorption to improve the condition of the skin. Thepresence of the hydrocarbon chain of the apolar acyl group bonded to theglutathione thiol group enables the compounds of the invention to beeffective as a topical application that can easily pass through thelipid bilayer of the cell membranes of epidermal and dermal cells.S-linoleoyl glutathione in particular has a lipophilic structure thatmakes it fat soluble and allows it to pass through cell membranes and beabsorbed directly into cells.

S-acyl glutathione compounds of the present invention may be prepared byvarious means known to those of skill in the art. For example, enzymatictransthioesterification can be achieved by reacting glutathione with anappropriate acyl ester of coenzyme A (CoA) followed by purification fromthe water phase by HPLC or by chemically reacting glutathione with thecorresponding acyl halide. See WO 2009/047728, supra, incorporatedherein by reference. Another synthesis may be carried out by reactingthe halide of the corresponding carboxylic acid with a solution ofL-glutathione in trifluoroacetic acid under vacuum, adding ethylacetate, and collecting the precipitated salt. See e.g. U.S. Pat. No.3,984,569, supra, which is hereby incorporated by reference.

Topical compositions containing S-acyl glutathiones according to thepresent invention are intended to be topically applied to and absorbedby the skin tissue. S-acyl glutathiones activate transketolase,increasing its activity by 300%, and prevent protein glycation and AGEformation. After treatment for the recommended period of time, it isexpected that decreased inflammation, irritation, and erythema of theskin will be observed, along with an increased skin elasticity andsuppleness. Fine lines and wrinkles should be reduced and skin coloringshould even out. The present invention thus is expected to prevent andtreat skin aging, address skin dryness, dullness, loss of elasticity andlack of radiance. Particularly, treatments may be used to prevent orretard the appearance of spider vessels or red blotchiness associatedwith menopausal skin. In another embodiment, treatments may be used toprevent or retard exaggerated lines and wrinkles.

Only effective amounts of topical compositions containing S-acylglutathione are needed to achieve the aforementioned benefits andprevent typical menopausal and aging effects on the skin. Generally,topical application to skin tissue is accomplished in association with adermatologically acceptable carrier, and particularly one in which theS-acyl glutathione is soluble per se or is effectively solubilized(e.g., as an emulsion or microemulsion). Where employed, the carrier isinert in the sense of not bringing about a deactivation or oxidation ofthe glutathione derived active ingredient(s), and in the sense of notbringing about any adverse effect on the skin areas to which it isapplied.

In one preferred practice of the invention, one or more S-acylglutathione derivatives is applied in admixture with thedermatologically acceptable carrier or vehicle (e.g., as a lotion,cream, ointment, soap, stick, or the like) so as to facilitate topicalapplication and, in some cases, provide additional therapeutic effectsas might be brought about, e.g., by moisturizing of the affected skinareas. While the carrier for the topical composition can consist of arelatively simple solvent or dispersant such as water, it is generallypreferred that the carrier comprise a composition more conducive totopical application, and particularly one which will form a film orlayer on the skin to which it is applied so as to localize theapplication and provide some resistance to washing off by immersion inwater or by perspiration and/or aid in the percutaneous delivery of theactive agent(s). Many preparations are known in the art, and includelotions containing oils and/or alcohols and emollients vegetable oils,hydrocarbon oils and waxes, silicone oils, animal or marine fats oroils, glyceride derivatives, fatty acids or fatty acid esters, oralcohols or alcohol ethers, lecithin, lanolin and derivatives,polyhydric alcohols or esters, wax esters, sterols, phospholipids andthe like, and generally also emulsifiers (nonionic, cationic oranionic), although some of the emollients inherently possess emulsifyingproperties. In the preferred embodiment, the carrier is lecithin.

As noted, these ingredients can be formulated into a cream, lotion, orgel, or a solid stick, by utilization of different proportions of theingredients and/or by inclusion of thickening agents such as gums orother forms of hydrophilic colloids. One possible embodiment is asolution used to saturate a pad used to wipe affected areas; another isa cleanser; and others are lotions, creams, and gels, which are referredto herein as dermally or dermatologically acceptable carriers, and areformulated using conventional techniques known to those of ordinaryskill in the art. The term “topical composition” as used herein shallmean the complete product including the S-acyl glutathione activeingredient, the carrier, and any adjuvants, thickeners, excipients, etc.as described herein which is applied to a person's skin.

The quantity of S-acyl glutathione active ingredient in the carrier maybe varied or adjusted widely depending upon the particular application,the potency of the particular compound or the desired concentration.Generally, the quantity of S-acyl glutathione active ingredient willrange between 0.01% to 20% by weight of the topical composition, morepreferably, 0.1% to 5% by weight. In some applications, the quantity ofS-acyl glutathione active ingredient will exceed 5% by weight. Indifferent embodiments, the weight percentage of S-acyl glutathione maybe in the range of 0.01%-0.025%; 0.025%-0.05%; 0.05%-0.10%; 0.10%-0.50%;0.50%-1.0%; 0.025%-0.50%; 0.025%-1.0%; 1.0%-2.0%; 2.0%-5.0%;5.0%-10.00%; 1.0%-5.0%; 1.0%-10.0%; 10.0%-20.0%; 10.0%-30.0%;10.0%-40.0%; 10.0%-50.0%; 10.0%-98.0%; 20.0%-30.0%; 20.0%-40.0%;30.0%-40.0%; 30.0%-60.0%; 40.0%-50.0%; 40.0%-70.0%; 50.0%-60.0%;50.0%-70.0%; 50.0%-80.0%; 60.0%-70.0%; 70.0%-80.0%; 80.0%-90.0%; or90.0%-98.0%. Generally, lower concentrations of S-acyl glutathioneactive ingredients in a carrier are suitable, depending upon theapplication regimen and the active and adjunct ingredients employed.

Generally in the practice of methods of the invention, the topicalcomposition is topically applied to the skin areas, such as that of theface, at predetermined intervals often as a moisturizer, tintedfoundation, cleanser, toner, lotion, cream, or gel, it generally beingthe case that gradual improvement is noted with each successiveapplication. Insofar as has been determined based upon clinical studiesto date, no adverse side effects are encountered. It is an advantage ofthe invention that compositions of the invention do not require apharmaceutical prescription.

The topical composition of the invention can contain additionalingredients commonly found in skin care compositions and cosmetics, suchas, for example, tinting agents, emollients, skin conditioning agents,emulsifying agents, humectants, preservatives, antioxidants, perfumes,chelating agents, etc., provided that they are physically and chemicallycompatible with other components of the composition. Preservativesinclude, but are not limited to, C₁-C₃ alkyl parabens andphenoxyenthanol, typically present in an amount ranging from about 0.1%to about 2.0% by weight percent, based on the total composition.Emollients, typically present in amounts ranging from about 0.01% to 5%of the total composition include, but are not limited to, fatty esters,fatty alcohols, mineral oils, polyether siloxane copolymers, andmixtures thereof. Humectants, typically present in amounts ranging fromabout 0.1% to about 5% by weight of the total composition include, butare not limited to, polyhydric alcohols such as glycerol, polyalkyleneglycols (e.g., butylene glycol, propylene glycol, dipropylene glycol,polypropylene glycol, and polyethylene glycol) and derivatives thereof,alkylene polyols and their derivatives, sorbitol, hydroxy sorbitol,hexylene glycol, 1,3-dibutylene glycol, 1,2,6-hexanetriol, ethoxylatedglycerol, propoxylated glycerol, and mixtures thereof. Emulsifiers,typically present in amounts from about 1% to about 10% by weight of thecomposition, include, but are not limited to, stearic acid, cetylalcohol, stearyl alcohol, steareth 2, steareth 20, acrylates/C10-30alkyl acrylate crosspolymers, and mixtures thereof. Chelating agents,typically present in amounts ranging from about 0.01% to about 2% byweight, include, but are not limited to, ethylenediamine tetraaceticacid (EDTA) and derivatives and salts thereof, dihydroxyethyl glycine,tartaric acid, and mixtures thereof. Antioxidants, typically present inan amount ranging from about 0.02% to about 0.5% by weight of thecomposition, include, but are not limited to, butylated hydroxy toluene(BHT); vitamin C and/or vitamin C derivatives, such as fatty acid estersof ascorbic acid, particularly ascorbyl palmitate; butylatedhydroanisole (BHA); phenyl-α-naphthylamine; hydroquinone; propylgallate; nordihydroquiaretic acid; vitamin E and/or derivatives ofvitamin E, including tocotrienol and/or tocotrienol derivatives; calciumpantothenates; green tea extracts; mixed polyphenols; and mixtures ofany of these. As mentioned above, particularly preferred antioxidantsare those that provide additional benefits to the skin such as ascorbylpalmitate.

Buffering agents are employed in many compositions. Preferably, theamount of buffering agent is one that results in compositions having apH ranging from about 4.5 to about 8.5, more preferably from about 5.5to about 8.5, most preferably from about 6.5 to about 8.0. Typicalbuffering agents are chemically and physically stable agents commonlyfound in cosmetics, and can include compounds that are also adjunctingredients such as citric acid, malic acid, and glycolic acid buffers.

Some embodiments of this invention contain at least one other adjunctingredient in addition to S-acyl glutathione. Adjunct ingredientsinclude, but are not limited to one or more of: lipoic acid; α-hydroxyacids such as glycolic acid or lactic acid; ascorbic acid and itsderivatives, especially fatty acid esters of ascorbic acid; ortocotrienols and tocotrienol derivatives and vitamin E compositionsenriched with tocotrienols or tocotrienol derivatives. Additionalingredients and methods as disclosed in my U.S. Pat. Nos. 5,376,361;5,409,693; 5,545,398; 5,554,647; 5,574,063; 5,643,586; 5,709,868;5,879,690; 6,191,121; 6,296,861; 6,437,004; and 6,979,459, which arehereby incorporated by reference, may also be used.

The above description is for the purpose of teaching the person ofordinary skill in the art how to practice the present invention, and itis not intended to detail all those obvious modifications and variationsof it which will become apparent to the skilled worker upon reading thedescription. It is intended, however, that all such obviousmodifications and variations be included within the scope of the presentinvention, which is defined by the following claims. The claims areintended to cover the claimed components and steps in any sequence whichis effective to meet the objectives there intended, unless the contextspecifically indicates the contrary.

1. A method of improving the appearance of peri-menopausal, menopausal,or post-menopausal skin comprising: applying to the skin tissue of amammal in need of such regulation, a safe and effective amount of acomposition containing S-acyl glutathione derivative of formula (I)

wherein R₁ consists of a saturated or unsaturated aliphatic C₁₂-C₂₄group and R₂ is a hydrogen, aliphatic or aromatic acyl group; and adermatologically acceptable carrier.
 2. The method of claim 1 wherein R₁is an unsaturated C₁₈ group.
 3. The method of claim 2 wherein R₁ is alinoleoyl or oleoyl group.
 4. The method of claim 1 comprising between0.01% to 20% by weight of S-acyl glutathione derivative.
 5. The methodof claim 4 comprising between 0.1% to 5% by weight of S-acyl glutathionederivative.
 6. The method of claim 1 comprising greater than 5% byweight of S-acyl glutathione.
 7. The method of claim 1 wherein thecarrier comprises lecithin.
 8. The method of claim 1 wherein saidcomposition further comprises one or more additional ingredientsselected from the group consisting of: ascorbic acid and ascorbic acidderivatives; lipoic acid; α-hydroxy acids; and tocotrienols andtocotrienol derivatives and vitamin E compositions enriched withtocotrienols or tocotrienol derivatives.
 9. The method of claim 1wherein severe skin dryness, dullness, or lack of radiance are improved.10. A method of preventing or retarding exaggerated lines and wrinklesof peri-menopausal, menopausal, or post-menopausal skin comprising:applying to the skin tissue of a mammal in need of such regulation, asafe and effective amount of a composition containing S-acyl glutathionederivative of formula (I)

wherein R₁ consists of a saturated or unsaturated aliphatic C₁₂-C₂₄group and R₂ is a hydrogen, aliphatic or aromatic acyl group; and adermatologically acceptable carrier.
 11. The method of claim 10 whereinR₁ is an unsaturated C₁₈ group.
 12. The method of claim 11 wherein R₁ isa linoleoyl or oleoyl group.
 13. The method of claim 10 comprisingbetween 0.01% to 20% by weight of S-acyl glutathione derivative.
 14. Themethod of claim 13 comprising between 0.1% to 5% by weight of S-acylglutathione derivative.
 15. The method of claim 10 comprising greaterthan 5% by weight of S-acyl glutathione.
 16. The method of claim 10wherein the carrier comprises lecithin.
 17. The method of claim 10wherein said composition further comprises one or more additionalingredients selected from the group consisting of: ascorbic acid andascorbic acid derivatives; lipoic acid; α-hydroxy acids; andtocotrienols and tocotrienol derivatives and vitamin E compositionsenriched with tocotrienols or tocotrienol derivatives.
 18. A method ofpreventing or retarding the appearance of spider vessels or redblotchiness in peri-menopausal, menopausal, or post-menopausal skincomprising: applying to the skin tissue of a mammal in need of suchregulation, a safe and effective amount of a composition containingS-acyl glutathione derivative of formula (I)

wherein R₁ consists of a saturated or unsaturated aliphatic C₁₂-C₂₄group and R₂ is a hydrogen, aliphatic or aromatic acyl group; and adermatologically acceptable carrier.
 19. The method of claim 18 whereinR₁ is an unsaturated C₁₈ group.
 20. The method of claim 19 wherein R₁ isa linoleoyl or oleoyl group.
 21. The method of claim 18 comprisingbetween 0.01% to 20% by weight of S-acyl glutathione derivative.
 22. Themethod of claim 21 comprising between 0.1% to 5% by weight of S-acylglutathione derivative.
 23. The method of claim 18 comprising greaterthan 5% by weight of S-acyl glutathione.
 24. The method of claim 18wherein the carrier comprises lecithin.
 25. The method of claim 18wherein said composition further comprises one or more additionalingredients selected from the group consisting of: ascorbic acid andascorbic acid derivatives; lipoic acid; α-hydroxy acids; andtocotrienols and tocotrienol derivatives and vitamin E compositionsenriched with tocotrienols or tocotrienol derivatives.
 26. A method ofimproving the appearance of peri-menopausal, menopausal, orpost-menopausal skin comprising: applying to the skin tissue of a mammalin need of such regulation, a safe and effective amount of a compositioncontaining S-linoleoyl glutathione in a dermatologically acceptablecarrier.
 27. The method of claim 26 comprising between 0.01% to 20% byweight of S-linoleoyl glutathione.
 28. The method of claim 27 comprisingbetween 0.1% to 5% by weight of S-linoleoyl glutathione.
 29. The methodof claim 26 comprising greater than 5% by weight of S-linoleoylglutathione.
 30. The method of claim 26 wherein said composition furthercomprises one or more additional ingredients selected from the groupconsisting of: ascorbic acid and ascorbic acid derivatives; lipoic acid;α-hydroxy acids; and tocotrienols and tocotrienol derivatives andvitamin E compositions enriched with tocotrienols or tocotrienolderivatives.
 31. The method of claim 26 wherein skin dryness, dullness,or lack of radiance are improved.
 32. The method of claim 26 whereinexaggerated lines and wrinkles are prevented or retarded.
 33. The methodof claim 26 wherein the appearance of spider vessels or red blotchinessis prevented or retarded.
 34. A method of improving the appearance ofperi-menopausal, menopausal, or post-menopausal skin comprising:applying to the skin tissue of a mammal in need of such regulation, asafe and effective amount of a composition containing reducedglutathione in a dermatologically acceptable carrier.